A glutamate receptor regulates Ca²⁺ mobilization in hippocampal neurons

We investigated the effect of various excitatory amino acids on intracellular free Ca²⁺ concentration ([Ca²⁺](i)) in single mouse hippocampal neurons in vitro by using the Ca²⁺-sensitive dye fura-2. In normal physiological solution, glutamate, kainate, N-methyl-D-aspartate, and quisqualate all produced increases in [Ca²⁺](i). When all extracellular Ca²⁺ was removed, kainate and N-methyl-D-aspartate were completely ineffective, but quisqualate and glutamate were able to produce a spike-like Ca²⁺ transient, presumably reflecting the release of Ca²⁺ from intracellular stores. Ca²⁺ transients of similar shape could also be produced by the α-adrenergic agonist phenylephrine. After the production of a Ca²⁺ transient a second addition of quisqualate was ineffective unless intracellular stores were refilled by loading the cells with Ca²⁺ following depolarization in Ca²⁺-containing medium. None of the conventional excitatory amino acid receptor antagonists inhibited the Ca²⁺-mobilizing effects of quisqualate. Furthermore α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) was unable to produce Ca²⁺ mobilization in Ca²⁺-free medium, although it could produce Ca²⁺ influx in Ca²⁺-containing medium. Thus, glutamate can produce mobilization of Ca²⁺ from intracellular stores in hippocampal neurons by acting on a quisqualate-sensitive but AMPA-insensitive receptor. This receptor is therefore distinct from the quisqualate receptor that produces cell depolarization. The possibility that this Ca²⁺-mobilizing effect is mediated by inositol triphosphate production is discussed.